Circulating blood is maintained in a delicate state of balance as long as it is flowing in undisturbed blood vessels lined by an intact endothelium. However, there are numerous situations where this balance is adversely affected so as to induce thrombosis, a life-threatening event that remains the number one man-killer if left untreated. On the other hand, if the reactions involved in the onset of thrombosis are set aside by too efficient inhibition excessive and life-threatening bleeding may occur.
It is generally accepted that the vascular wall facing blood should be covered by an undamaged monolayer of endothelial cells. This cell layer is covered by network of membrane-bound proteoglycans and glycoproteins, referred to as the endothelial glycocalyx. Over the last decade, the endothelial glycocalyx has increasingly been appreciated as an intravascular compartment that protects the vessel wall against pathogenic insults. Damage to the endothelial glycocalyx has been shown to enhance adhesion of leucytes and platelets to the vascular endothelium, and also to induce endothelial dysfunction due to disturbed mechanotransducing effects. Significant disturbance of the endothelial glycocalyx has been reported to be associated with e.g. diabetes, ischemia/reperfusion and atherosclerosis.
Today vessel wall damages caused by dilation or other surgical procedures and diseases are treated by systemic administration of various drugs.
Heparin has a long record as a clinically accepted anticoagulant by acting as a potent accelerator of antithrombin, a naturally occurring protein in blood that is capable of inhibiting a number of coagulation enzymes including thrombin. Hirudin is an example of a direct inhibitor of thrombin. The use of heparin or hirudin is associated with a less than negligible risk of bleeding.
A macromolecular conjugate composed of multiple heparin chains covalently linked to an inert main chain has been utilized for modifying both artificial (WO93/05793) and biological surfaces (WO00/45837) in such a way that these surfaces present permanently surface-bound heparin so as to mimic the chemical constitution of the blood vessel endothelium, which carries surface localised heparan sulphate.